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Abstract Background Brain metastasis from prostate adenocarcinoma (PCa) is rare, often leading to death within a year. Its infrequent occurrence and atypical histopathologic features contribute to lower consideration in the differential diagnosis of tumor brain metastasis. This study aims to assess the clinical characteristics and distinctive histopathologic features of metastatic PCa in the brain for timely and enhanced diagnostic accuracy. Design A retrospective search spanning 20 years (2003–2022) was conducted on our archives and identified 21 cases diagnosed as “metastatic prostate adenocarcinoma (mPCa)” in brain biopsies and resections. All existing slides were thoroughly reviewed to evaluate the histopathology of the mPCa. Result The mean age at presentation for brain metastasis was 70 years. Of 21 cases, 5 were dural-based lesions, 16 were true intraparenchymal metastases, including 2 sellar/suprasellar masses, 3 frontal, 3 temporal, 3 occipital, 1 cerebellum, and 4 involving multiple brain lobes. The average interval between initial diagnosis and brain metastasis was 90.75 months. Notably, brain metastasis was the initial presentation for one patient, while another patient, initially diagnosed with prognostic grade group (GG) 2 PCa in 1/12 cores, presented with isolated brain metastasis two years later. Architecturally, tumor cells were arranged in sheets or nests in most cases; however, four cases showed histologic cribriform patterns, and five displayed papillary architecture. Cytohistology varied from uniform monomorphic to highly pleomorphic cells with prominent nucleoli (8/19) and high mitotic activity. Interestingly, 1 case showed small round blue cell morphology, another had focal areas of rhabdoid and spindle cell differentiation, and 6 had cytoplasmic clearing. Almost half of the cases (47%) showed necrosis. Conclusion mPCa to the brain can present with variable histomorphology. Therefore, consideration of mPCa in the differential diagnosis of metastatic brain lesions, even with non-suggestive imaging, is imperative in male patients with or without a history of primary disease. Accurate and prompt diagnosis is crucial, given the recent advancements in treatment that have improved survival rates.

Abstract This study aimed to investigate the simultaneous response of the cerebral and skeletal muscle microvasculature to the same phenylephrine (PE) boluses. A hybrid optical system that combines hyperspectral near‐infrared spectroscopy (hs‐NIRS) and diffuse correlation spectroscopy (DCS) was used to monitor changes in tissue oxygenation and perfusion. Data were collected from the head and hind limb of seven male Sprague–Dawley rats while administering intravenous (IV) injections of PE or saline to all animals. The response to saline was used as a control. Skeletal muscle oxygenation decreased significantly after PE injection, while a statistically underpowered decrease in perfusion was observed, followed by an increase beyond baseline. Vascular conductance also decreased in the muscle reflecting the drug's vasoconstrictive effects. Tissue oxygenation and perfusion increased in the brain in response to PE. Initially, there was a sharp increase in cerebral perfusion but no changes in cerebral vascular conductance. Subsequently, cerebral flow and vascular conductance decreased significantly below baseline, likely reflecting autoregulatory mechanisms to manage the excess flow. Further, fitting an exponential function to the secondary decrease in cerebral perfusion and increase in muscular blood flow revealed a quicker kinetic response in the brain to adjust blood flow. In the skeletal muscle, PE caused a transient decrease in blood volume due to vasoconstriction, which resulted in an overall decrease in hemoglobin content and tissue oxygen saturation. Since PE does not directly affect cerebral vessels, this peripheral vasoconstriction shunted blood into the brain, resulting in an initial increase in oxygenated hemoglobin and oxygen saturation.

Abstract Background and objective Autosomal recessive genetic disorders pose significant health challenges in regions where consanguineous marriages are prevalent. The utilization of exome sequencing as a frequently employed methodology has enabled a clear delineation of diagnostic efficacy and mode of inheritance within multiplex consanguineous families. However, these aspects remain less elucidated within simplex families. Methods In this study involving 12 unrelated simplex Iranian families presenting syndromic autism, we conducted singleton exome sequencing. The identified genetic variants were validated using Sanger sequencing, and for the missense variants in FOXG1 and DMD, 3D protein structure modeling was carried out to substantiate their pathogenicity. To examine the expression patterns of the candidate genes in the fetal brain, adult brain, and muscle, RT-qPCR was employed. Results In four families, we detected an autosomal dominant gene (FOXG1), an autosomal recessive gene (CHKB), and two X-linked autism genes (IQSEC2 and DMD), indicating diverse inheritance patterns. In the remaining eight families, we were unable to identify any disease-associated genes. As a result, our variant detection rate stood at 33.3% (4/12), surpassing rates reported in similar studies of smaller cohorts. Among the four newly identified coding variants, three are de novo (heterozygous variant p.Trp546Ter in IQSEC2, heterozygous variant p.Ala188Glu in FOXG1, and hemizygous variant p.Leu211Met in DMD), while the homozygous variant p.Glu128Ter in CHKB was inherited from both healthy heterozygous parents. 3D protein structure modeling was carried out for the missense variants in FOXG1 and DMD, which predicted steric hindrance and spatial inhibition, respectively, supporting the pathogenicity of these human mutants. Additionally, the nonsense variant in CHKB is anticipated to influence its dimerization – crucial for choline kinase function – and the nonsense variant in IQSEC2 is predicted to eliminate three functional domains. Consequently, these distinct variants found in four unrelated individuals with autism are likely indicative of loss-of-function mutations. Conclusions In our two syndromic autism families, we discovered variants in two muscular dystrophy genes, DMD and CHKB. Given that DMD and CHKB are recognized for their participation in the non-cognitive manifestations of muscular dystrophy, it indicates that some genes transcend the boundary of apparently unrelated clinical categories, thereby establishing a novel connection between ASD and muscular dystrophy. Our findings also shed light on the complex inheritance patterns observed in Iranian consanguineous simplex families and emphasize the connection between autism spectrum disorder and muscular dystrophy. This underscores a likely genetic convergence between neurodevelopmental and neuromuscular disorders.

Abstract Background Behavioral or mental health disorders are common in children, adolescents, and young adults. Medication use is increasingly common, with few data describing drug-drug combinations in ambulatory settings. The objectives of this study were to describe the pharmaco-epidemiology of behavioral and mental health (BMH) medications among children, adolescents, and young adults in New York Medicaid and assess the prevalence of contraindicated drug pairs within this population. Methods This observational cross-sectional study evaluated New York State Medicaid managed care and fee-for-service enrollees under 21 years of age dispensed BMH medications in 2014. Main outcomes included number of members with prescriptions filled; number filling > 1 medication prescription concurrently for ≥ 30 days (polypharmacy), and number and nature of potentially contraindicated drug pairs. Results Of 2,430,434 children, adolescents, and young adults, 422,486 (17.4%) had a visit associated with a BMH diagnosis and 141,363 (5.8%) received one or more BMH medications. With 84 distinct medications evaluated, polypharmacy was common, experienced by 53,388 individuals (37.8% of those with a prescription filled), generating 11,115 distinct drug combinations. 392 individuals filled prescriptions for a contraindicated pair of ≥ 2 BMH medications for 30 days or longer. With ≥ 1 day overlap, 651 were exposed to contraindicated medications. The most common contraindicated pairs increased potential risk for prolonged QT interval and serotonin syndrome (n = 378 and n = 250 patients, respectively). Most combinations involved ziprasidone (3247.1 per 10,000 ziprasidone prescriptions filled). Conclusions With nearly 6% of members dispensed a BMH medication, contraindicated drug pairs were uncommon. However, any of those combinations represent a potential risk. Clinicians should attend to the balance of potential risks and benefits before contraindicated pairs are dispensed. The methodology described could serve as a basis for monitoring such rare instances and might reduce harm.

Abstract Background Gestational exposure to toxic environmental chemicals and maternal social hardships are individually associated with impaired fetal growth, but it is unclear whether the effects of environmental chemical exposure on infant birth weight are modified by maternal hardships. Methods We used data from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a pan-Canadian cohort of 1982 pregnant females enrolled between 2008 and 2011. We quantified eleven environmental chemical concentrations from two chemical classes – six organochlorine compounds (OCs) and five metals – that were detected in ≥ 70% of blood samples collected during the first trimester. We examined fetal growth using birth weight adjusted for gestational age and assessed nine maternal hardships by questionnaire. Each maternal hardship variable was dichotomized to indicate whether the females experienced the hardship. In our analysis, we used elastic net to select the environmental chemicals, maternal hardships, and 2-way interactions between maternal hardships and environmental chemicals that were most predictive of birth weight. Next, we obtained effect estimates using multiple linear regression, and plotted the relationships by hardship status for visual interpretation. Results Elastic net selected trans-nonachlor, lead, low educational status, racially minoritized background, and low supplemental folic acid intake. All were inversely associated with birth weight. Elastic net also selected interaction terms. Among those with increasing environmental chemical exposures and reported hardships, we observed stronger negative associations and a few positive associations. For example, every two-fold increase in lead concentrations was more strongly associated with reduced infant birth weight among participants with low educational status (β = -100 g (g); 95% confidence interval (CI): -215, 16), than those with higher educational status (β = -34 g; 95% CI: -63, -3). In contrast, every two-fold increase in mercury concentrations was associated with slightly higher birth weight among participants with low educational status (β = 23 g; 95% CI: -25, 71) compared to those with higher educational status (β = -9 g; 95% CI: -24, 6). Conclusions Our findings suggest that maternal hardships can modify the associations of gestational exposure to some OCs and metals with infant birth weight.

Viral respiratory illness surveillance has traditionally focused on single pathogens (e.g., influenza) and required fever to identify influenza-like illness (ILI). We developed an automated system applying both laboratory test and syndrome criteria to electronic health records from 3 practice groups in Massachusetts, USA, to monitor trends in respiratory viral–like illness (RAVIOLI) across multiple pathogens. We identified RAVIOLI syndrome using diagnosis codes associated with respiratory viral testing or positive respiratory viral assays or fever. After retrospectively applying RAVIOLI criteria to electronic health records, we observed annual winter peaks during 2015–2019, predominantly caused by influenza, followed by cyclic peaks corresponding to SARS-CoV-2 surges during 2020–2024, spikes in RSV in mid-2021 and late 2022, and recrudescent influenza in late 2022 and 2023. RAVIOLI rates were higher and fluctuations more pronounced compared with traditional ILI surveillance. RAVIOLI broadens the scope, granularity, sensitivity, and specificity of respiratory viral illness surveillance compared with traditional ILI surveillance.

The COVID-19 pandemic has highlighted the need to upgrade systems for infectious disease surveillance and forecasting and modeling of the spread of infection, both of which inform evidence-based public health guidance and policies. Here, we discuss requirements for an effective surveillance system to support decision making during a pandemic, drawing on the lessons of COVID-19 in the U.S., while looking to jurisdictions in the U.S. and beyond to learn lessons about the value of specific data types. In this report, we define the range of decisions for which surveillance data are required, the data elements needed to inform these decisions and to calibrate inputs and outputs of transmission-dynamic models, and the types of data needed to inform decisions by state, territorial, local, and tribal health authorities. We define actions needed to ensure that such data will be available and consider the contribution of such efforts to improving health equity.

Porphyry-type Cu ± Au ± Mo deposits form in the upper (ca. 2–5 km deep) parts of large, long-lived magmatic-hydrothermal systems in which mineralising fluids are thought to be derived from mid-to shallow-crustal magma chambers. Increasingly, however, magmatic systems are viewed as consisting of mush with minor and transient lenses of magma, with mush being a variably packed framework of crystals with interstitial melt and magmatic volatile phase (MVP). In this context, questions remain as to the source (mainly depth) and mechanisms of transport and focussing of the vast volumes of fluids required for shallow level porphyry-type mineralisation. Even more problematic is a paucity of first-order textural evidence for the presence of mush in magmatic-hydrothermal systems, including those which host porphyry-type deposits. To address this, we have studied the aplitic porphyry cupola of the Saginaw Hill magmatic system, Tuscon, Arizona, United States, where magmatic-hydrothermal features are exceptionally well exposed, including a massive silica cap, quartz unidirectional solidification textures (USTs), stockworks of multiple generations of variably mineralised quartz veins and mineralised miarolitic cavities. From field-to micro-scale textural and geochemical studies, particularly observations of vermiform quartz between earlier generations of magmatic quartz and feldspar, we evidence the development of fluid pathways through mush at the magmatic-hydrothermal transition. These are shown to connect and provide fluids and ore constituents to the mineralised miarolitic cavities and early quartz vein stockworks. We suggest that this process should be considered in all new genetic, exploration and numerical models for porphyry and similar types of magmatic-hydrothermal ore-deposits.

Previous research on climate-relevant knowledge distinguishes between two types: belief-linked (facts which can be guessed based on general climate beliefs) and belief-neutral (facts which require specific knowledge). To better understand these differences, we used data from nationwide US 2016 and 2021 surveys to develop composite indicators of the two types of knowledge. We analyzed demographic predictors of each type, as well as their effect on climate change belief. Further, we examined the issue of trust in science. The findings point to some novel insights. One, not all knowledge is equal; specific, belief-neutral knowledge in particular is less necessary for climate change belief. And two, trust in science is more relevant for fostering climate change belief than either knowledge type. Although this poses certain challenges, given the ideological divide when it comes to scientific trust, it is also useful information for policymakers and science communicators about where to direct energy and resources when engaging with the public.

Abstract Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) possess tremendous potential for basic research and translational application. However, these cells structurally and functionally resemble fetal cardiomyocytes, which is a major limitation of these cells. Microgravity can significantly alter cell behavior and function. Here we investigated the effect of simulated microgravity on hiPSC-CM maturation. Following culture under simulated microgravity in a random positioning machine for 7 days, 3D hiPSC-CMs had increased mitochondrial content as detected by a mitochondrial protein and mitochondrial DNA to nuclear DNA ratio. The cells also had increased mitochondrial membrane potential. Consistently, simulated microgravity increased mitochondrial respiration in 3D hiPSC-CMs, as indicated by higher levels of maximal respiration and ATP content, suggesting improved metabolic maturation in simulated microgravity cultures compared with cultures under normal gravity. Cells from simulated microgravity cultures also had improved Ca2+ transient parameters, a functional characteristic of more mature cardiomyocytes. In addition, these cells had improved structural properties associated with more mature cardiomyocytes, including increased sarcomere length, z-disc length, nuclear diameter, and nuclear eccentricity. These findings indicate that microgravity enhances the maturation of hiPSC-CMs at the structural, metabolic, and functional levels.

Abstract Background Cardiac pathological outcome of metabolic remodeling is difficult to model using cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) due to low metabolic maturation. Methods hiPSC-CM spheres were treated with AMP-activated protein kinase (AMPK) activators and examined for hiPSC-CM maturation features, molecular changes and the response to pathological stimuli. Results Treatment of hiPSC-CMs with AMPK activators increased ATP content, mitochondrial membrane potential and content, mitochondrial DNA, mitochondrial function and fatty acid uptake, indicating increased metabolic maturation. Conversely, the knockdown of AMPK inhibited mitochondrial maturation of hiPSC-CMs. In addition, AMPK activator-treated hiPSC-CMs had improved structural development and functional features—including enhanced Ca2+ transient kinetics and increased contraction. Transcriptomic, proteomic and metabolomic profiling identified differential levels of expression of genes, proteins and metabolites associated with a molecular signature of mature cardiomyocytes in AMPK activator-treated hiPSC-CMs. In response to pathological stimuli, AMPK activator-treated hiPSC-CMs had increased glycolysis, and other pathological outcomes compared to untreated cells. Conclusion AMPK activator-treated cardiac spheres could serve as a valuable model to gain novel insights into cardiac diseases.

Abstract Background Endogenous estrogen is cardio-protective in healthy premenopausal women. Despite this favorable action of estrogen, animal models depict a detrimental effect of estradiol on vascular function in the presence of diabetes. The present study sought to determine the role of endogenous estradiol on endothelial function in women with type 1 diabetes. Method 32 women with type 1 diabetes (HbA1c = 8.6 ± 1.7%) and 25 apparently healthy women (HbA1c = 5.2 ± 0.3%) participated. Flow-mediated dilation (FMD), a bioassay of nitric-oxide bioavailability and endothelial function was performed during menses (M) and the late follicular (LF) phase of the menstrual cycle to represent low and high concentrations of estrogen, respectively. In addition, a venous blood sample was collected at each visit to determine circulating concentrations of estradiol, thiobarbituric acid reactive substances (TBARS), and nitrate/nitrite (NOx), biomarkers of oxidative stress and nitric oxide, respectively. Data were collected in (1) 9 additional women with type 1 diabetes using oral hormonal birth control (HBC) (HbA1c = 8.3 ± 2.1%) during the placebo pill week and second active pill week, and (2) a subgroup of 9 demographically matched women with type 1 diabetes not using HBC (HbA1c = 8.9 ± 2.1%). Results Overall, estradiol was significantly increased during the LF phase compared to M in both type 1 diabetes (Δestradiol = 75 ± 86 pg/mL) and controls (Δestradiol = 71 ± 76 pg/mL); however, an increase in TBARS was only observed in patients with type 1 diabetes (ΔTBARS = 3 ± 13 µM) compared to controls (ΔTBARS = 0 ± 4 µM). FMD was similar (p = 0.406) between groups at M. In addition, FMD increased significantly from M to the LF phase in controls (p = 0.024), whereas a decrease was observed in type 1 diabetes. FMD was greater (p = 0.015) in patients using HBC compared to those not on HBC, independent of menstrual cycle phase. Conclusion Endogenous estradiol increases oxidative stress and contributes to endothelial dysfunction in women with diabetes. Additionally, HBC use appears to be beneficial to endothelial function in type 1 diabetes.

Abstract In a patient diagnosed with both Kallmann syndrome (KS) and intellectual disability (ID), who carried an apparently balanced translocation t(7;12)(q22;q24)dn, array comparative genomic hybridization (aCGH) disclosed a cryptic heterozygous 4.7 Mb deletion del(12)(p11.21p11.23), unrelated to the translocation breakpoint. This novel discovery prompted us to consider the possibility that the combination of KS and neurological disorder in this patient could be attributed to gene(s) within this specific deletion at 12p11.21-12p11.23, rather than disrupted or dysregulated genes at the translocation breakpoints. To further support this hypothesis, we expanded our study by screening five candidate genes at both breakpoints of the chromosomal translocation in a cohort of 48 KS patients. However, no mutations were found, thus reinforcing our supposition. In order to delve deeper into the characterization of the 12p11.21-12p11.23 region, we enlisted six additional patients with small copy number variations (CNVs) and analyzed eight individuals carrying small CNVs in this region from the DECIPHER database. Our investigation utilized a combination of complementary approaches. Firstly, we conducted a comprehensive phenotypic-genotypic comparison of reported CNV cases. Additionally, we reviewed knockout animal models that exhibit phenotypic similarities to human conditions. Moreover, we analyzed reported variants in candidate genes and explored their association with corresponding phenotypes. Lastly, we examined the interacting genes associated with these phenotypes to gain further insights. As a result, we identified a dozen candidate genes: TSPAN11 as a potential KS candidate gene, TM7SF3, STK38L, ARNTL2, ERGIC2, TMTC1, DENND5B, and ETFBKMT as candidate genes for the neurodevelopmental disorder, and INTS13, REP15, PPFIBP1, and FAR2 as candidate genes for KS with ID. Notably, the high-level expression pattern of these genes in relevant human tissues further supported their candidacy. Based on our findings, we propose that dosage alterations of these candidate genes may contribute to sexual and/or cognitive impairments observed in patients with KS and/or ID. However, the confirmation of their causal roles necessitates further identification of point mutations in these candidate genes through next-generation sequencing.

Safe landings are imperative to accomplish NASA’s Artemis goal to enable human exploration on the Moon, including sample collection missions. However, a process known as plume surface interaction (PSI) presents a significant hazard to lunar landings. PSI occurs when the engine exhaust of a lander interacts with the surface ejecting large amounts of regolith particles at high velocities that can interfere with the landing, disturb the surface, and damage hardware. To better understand PSI, the particle impact event (PIE) sensor is being developed to measure the kinetic energy and the flux of ejecta during landings, to quantify the potential damage, and to quantify the ejecta displaced. Multiple parameters were estimated to define the PIE instrument requirements. These estimates demonstrate that ejecta can travel at velocities of up to 800 m/s and impact the surrounding area with energies of up to 400 µJ. A significant amount of ejecta can be deposited several 10 s of meters away from the landing site, modifying the surface and causing dust-related challenges. The PIE sensor will be launched for the first time in an upcoming lunar lander. Then, PIE measurements will be used to improve PSI prediction capabilities and develop mitigation strategies to ensure safe landings.

Abstract WDR11, a gene associated with Kallmann syndrome, is important in reproductive system development but molecular understanding of its action remains incomplete. We previously reported that Wdr11-deficient embryos exhibit defective ciliogenesis and developmental defects associated with Hedgehog (HH) signalling. Here we demonstrate that WDR11 is required for primordial germ cell (PGC) development, regulating canonical and noncanonical HH signalling in parallel. Loss of WDR11 disrupts PGC motility and proliferation driven by the cilia-independent, PTCH2/GAS1-dependent noncanonical HH pathway. WDR11 modulates the growth of somatic cells surrounding PGCs by regulating the cilia-dependent, PTCH1/BOC-dependent canonical HH pathway. We reveal that PTCH1/BOC or PTCH2/GAS1 receptor context dictates SMO localisation inside or outside of cilia, respectively, and loss of WDR11 affects the signalling responses of SMO in both situations. We show that GAS1 is induced by PTCH2-specific HH signalling, which is lost in the absence of WDR11. We also provide evidence supporting a role for WDR11 in ciliogenesis through regulation of anterograde intraflagellar transport potentially via its interaction with IFT20. Since WDR11 is a target of noncanonical SMO signalling, WDR11 represents a novel mechanism by which noncanonical and canonical HH signals communicate and cooperate.

Abstract Background Dupuytren’s disease (DD) is a fibroproliferative hand disorder associated with various medical conditions, including diabetes mellitus (DM). The reported prevalence of DM among DD patients varies widely, primarily due to small sample sizes in previous studies. Methods This was a retrospective cohort study using data from the TriNetX Research Database. We analyzed the overall prevalence of DD between 2010 and 2020, comparing the DM, type 1 diabetes mellitus (T1DM), and type 2 diabetes mellitus (T2DM) cohorts. Within the DM group, patients were further categorized based on hemoglobin A1c (HbA1c) values and prescribed anti-diabetic agents (insulin or metformin). We compared the prevalence of DD diagnosis in each group using prevalence ratios and differences. Results There is a higher prevalence of DD in patients with T2DM than in patients with T1DM (relative risk [RR]: 1.641; 95% confidence interval [CI]: [1.356, 1.986]). Among patients with diabetes, there is a higher prevalence of DD in those taking insulin compared to those taking metformin (RR: 0.801, 95% CI: [0.774, 0.83]). The prevalence of DD varies depending on HbA1c levels, with a prevalence of 0.463% in patients having levels within the diabetic range, while lower prevalences of 0.392% and 0.416% are found in patients with prediabetes or uncontrolled diabetes, respectively. Conclusions This study provides further insight into the relationship between DM and DD. These findings may be attributed to the increased accumulation of advanced glycosylated end products (AGEs) in patients with diabetes. Future research exploring the connection between AGE accumulation and DD development may enhance our understanding of the relationship between DD and DM.

Abstract The Greater Bay Area (GBA) is to become a major innovation and technology hub of global impact. Such a transformation is to take place in the midst of a policy-driven economy in GBA’s Mainland region and a market-driven economy in Hong Kong and Macau. In this paper, we examine the uniqueness and complexities of logistics and trade facilitation in GBA. This study establishes a discourse in GBA’s logistics and trade facilitation between government and non-government stakeholders. Based on the discourse, we provide a conceptual context on the unique aspects of GBA, pinpointing critical issues such as the coexistence of differing institutional systems and interplay between state planning and market economy. A major objective of the paper is to identify and conceptualize unique logistics and trade features of GBA development, and to highlight opportunities for academic and policy research.

Purpose: The etiopathogenesis of coronal nonsyndromic craniosynostosis (cNCS), a congenital condition defined by premature fusion of 1 or both coronal sutures, remains largely unknown. Methods: We conducted the largest genome-wide association study of cNCS followed by replication, fine mapping, and functional validation of the most significant region using zebrafish animal model. Results: Genome-wide association study identified 6 independent genome-wide-significant risk alleles, 4 on chromosome 7q21.3 SEM1-DLX5-DLX6 locus, and their combination conferred over 7-fold increased risk of cNCS. The top variants were replicated in an independent cohort and showed pleiotropic effects on brain and facial morphology and bone mineral density. Fine mapping of 7q21.3 identified a craniofacial transcriptional enhancer (eDlx36) within the linkage region of the top variant (rs4727341; odds ratio [95% confidence interval], 0.48[0.39-0.59]; P = 1.2E−12) that was located in SEM1 intron and enriched in 4 rare risk variants. In zebrafish, the activity of the transfected human eDlx36 enhancer was observed in the frontonasal prominence and calvaria during skull development and was reduced when the 4 rare risk variants were introduced into the sequence. Conclusion: Our findings support a polygenic nature of cNCS risk and functional role of craniofacial enhancers in cNCS susceptibility with potential broader implications for bone health.

Although the hazards posed by greenhouse warming and COVID-19 are quite different, diagnosis and mitigation prospects for both depend heavily on science. Unfortunately, the reality of both threats has been subject to politicized science rejection in the US, making these deadly problems less tractable. There are substantial parallels between the two cases of science rejection, including common rhetoric and conservative political leadership. Survey research has reached widely-replicated conclusions regarding the social bases of climate-change perceptions. Corresponding studies of COVID-19 perceptions have found some political commonalities, but less agreement on other details. Here, we address this gap using generalized structural equation modeling (GSEM) and 2021 US survey data to make direct comparisons between the social bases of rejecting the reality of anthropogenic climate change (ACC) and rejecting COVID-19 vaccination. Trumpism, operationalized from approval of ex-president Trump, is viewed as an intervening variable that influences both types of science rejection. Trumpism itself is predicted by age, race, evangelical religion, ideology, and receptivity to seemingly non-political conspiracy beliefs. Considering direct as well as indirect effects (through Trumpism), climate change and vaccine rejection are similarly predicted by white and evangelical identity, conspiracism, and by education×ideology and friends×party interactions. The finding that Trumpism exacerbates science rejection could also apply to other science- and expertise-related topics unrelated to climate and COVID. These results invite broader comparisons across topics, with analogous movements in other countries, and continued tracking as US Trumpism evolves beyond Trump.

Abstract The founder population of Newfoundland and Labrador (NL) is a unique genetic resource, in part due to its geographic and cultural isolation, where historical records describe a migration of European settlers, primarily from Ireland and England, to NL in the 18th and 19th centuries. Whilst its historical isolation, and increased prevalence of certain monogenic disorders are well appreciated, details of the fine-scale genetic structure and ancestry of the population are lacking. Understanding the genetic origins and background of functional, disease causing, genetic variants would aid genetic mapping efforts in the Province. Here, we leverage dense genome-wide SNP data on 1,807 NL individuals to reveal fine-scale genetic structure in NL that is clustered around coastal communities and correlated with Christian denomination. We show that the majority of NL European ancestry can be traced back to the south-east and south-west of Ireland and England, respectively. We date a substantial population size bottleneck approximately 10-15 generations ago in NL, associated with increased haplotype sharing and autozygosity. Our results reveal insights into the population history of NL and demonstrate evidence of a population conducive to further genetic studies and biomarker discovery.

Abstract Background Hemangioblastoma of the central nervous system is an uncommon benign neoplasm, with about 25% of cases in patients with von Hippel–Lindau disease. The incidence of metastasis is rare, particularly in patients without von Hippel–Lindau disease. We report a case of hemangioblastoma with leptomeningeal dissemination as a late recurrence. Case presentation A 65-year-old Caucasian man with a history of World Health Organization grade I hemangioblastoma of the cerebellar vermis underwent gross total resection in 1997. In early 2018, he developed intracranial recurrences with diffuse leptomeningeal disease of the entire spine. The patient underwent resection of intracranial recurrence, followed by palliative craniospinal irradiation. The disease progressed quickly, and he died 8 months after recurrence. Conclusions Despite a benign pathology, hemangioblastoma has a low risk of metastasis. The outcome for hemangioblastoma patients with metastasis is poor. Multidisciplinary care for patients with metastatic hemangioblastoma warrants further investigation, and an effective systemic option is urgently needed. Regular lifelong follow-up of at-risk patients is recommended.

Leaf disease recognition using image processing and deep learning techniques is currently a vibrant research area. Most studies have focused on recognizing diseases from images of whole leaves. This approach limits the resulting models’ ability to estimate leaf disease severity or identify multiple anomalies occurring on the same leaf. Recent studies have demonstrated that classifying leaf diseases based on individual lesions greatly enhances disease recognition accuracy. In those studies, however, the lesions were laboriously cropped by hand. This study proposes a semi-automatic algorithm that facilitates the fast and efficient preparation of datasets of individual lesions and leaf image pixel maps to overcome this problem. These datasets were then used to train and test lesion classifier and semantic segmentation Convolutional Neural Network (CNN) models, respectively. We report that GoogLeNet’s disease recognition accuracy improved by more than 15% when diseases were recognized from lesion images compared to when disease recognition was done using images of whole leaves. A CNN model which performs semantic segmentation of both the leaf and lesions in one pass is also proposed in this paper. The proposed KijaniNet model achieved state-of-the-art segmentation performance in terms of mean Intersection over Union (mIoU) score of 0.8448 and 0.6257 for the leaf and lesion pixel classes, respectively. In terms of mean boundary F1 score, the KijaniNet model attained 0.8241 and 0.7855 for the two pixel classes, respectively. Lastly, a fully automatic algorithm for leaf disease recognition from individual lesions is proposed. The algorithm employs the semantic segmentation network cascaded to a GoogLeNet classifier for lesion-wise disease recognition. The proposed fully automatic algorithm outperforms competing methods in terms of its superior segmentation and classification performance despite being trained on a small dataset.

A reduction in wake effects in large wind farms through wake-aware control has considerable potential to improve farm efficiency. This work examines the success of several emerging, empirically derived control methods that modify wind turbine wakes (i.e., the pulse method, helix method, and related methods) based on Strouhal numbers on the O(0.3). Drawing on previous work in the literature for jet and bluff-body flows, the analyses leverage the normal-mode representation of wake instabilities to characterize the large-scale wake meandering observed in actuated wakes. Idealized large-eddy simulations (LES) using an actuator-line representation of the turbine blades indicate that the n=0 and ±1 modes, which correspond to the pulse and helix forcing strategies, respectively, have faster initial growth rates than higher-order modes, suggesting these lower-order modes are more appropriate for wake control. Exciting these lower-order modes with periodic pitching of the blades produces increased modal growth, higher entrainment into the wake, and faster wake recovery. Modal energy gain and the entrainment rate both increase with streamwise distance from the rotor until the intermediate wake. This suggests that the wake meandering dynamics, which share close ties with the relatively well-characterized meandering dynamics in jet and bluff-body flows, are an essential component of the success of wind turbine wake control methods. A spatial linear stability analysis is also performed on the wake flows and yields insights on the modal evolution. In the context of the normal-mode representation of wake instabilities, these findings represent the first literature examining the characteristics of the wake meandering stemming from intentional Strouhal-timed wake actuation, and they help guide the ongoing work to understand the fluid-dynamic origins of the success of the pulse, helix, and related methods.

This study investigated the genetic underpinnings of autism spectrum disorder (ASD) in a Middle Eastern cohort in Qatar using exome sequencing. The study identified six candidate autism genes in independent simplex families, including both four known and two novel autosomal dominant and autosomal recessive genes associated with ASD. The variants consisted primarily of de novo and homozygous missense and splice variants. Multiple individuals displayed more than one candidate variant, suggesting the potential involvement of digenic or oligogenic models. These variants were absent in the Genome Aggregation Database (gnomAD) and exhibited extremely low frequencies in the local control population dataset. Two novel autism genes, TRPC4 and SCFD2, were discovered in two Qatari autism individuals. Furthermore, the D651A substitution in CLCN3 and the splice acceptor variant in DHX30 were identified as likely deleterious mutations. Protein modeling was utilized to evaluate the potential impact of three missense variants in DEAF1, CLCN3, and SCFD2 on their respective structures and functions, which strongly supported the pathogenic natures of these variants. The presence of multiple de novo mutations across trios underscored the significant contribution of de novo mutations to the genetic etiology of ASD. Functional assays and further investigations are necessary to confirm the pathogenicity of the identified genes and determine their significance in ASD. Overall, this study sheds light on the genetic factors underlying ASD in Qatar and highlights the importance of considering diverse populations in ASD research.

Summary: Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect (CHD) characterized by hypoplasia of the left ventricle and aorta along with stenosis or atresia of the aortic and mitral valves. HLHS represents only ∼4%–8% of all CHDs but accounts for ∼25% of deaths. HLHS is an isolated defect (i.e., iHLHS) in 70% of families, the vast majority of which are simplex. Despite intense investigation, the genetic basis of iHLHS remains largely unknown. We performed exome sequencing on 331 families with iHLHS aggregated from four independent cohorts. A Mendelian-model-based analysis demonstrated that iHLHS was not due to single, large-effect alleles in genes previously reported to underlie iHLHS or CHD in >90% of families in this cohort. Gene-based association testing identified increased risk for iHLHS associated with variation in CAPN2 (p = 1.8 × 10−5), encoding a protein involved in functional adhesion. Functional validation studies in a vertebrate animal model (Xenopus laevis) confirmed CAPN2 is essential for cardiac ventricle morphogenesis and that in vivo loss of calpain function causes hypoplastic ventricle phenotypes and suggest that human CAPN2707C>T and CAPN21112C>T variants, each found in multiple individuals with iHLHS, are hypomorphic alleles. Collectively, our findings show that iHLHS is typically not a Mendelian condition, demonstrate that CAPN2 variants increase risk of iHLHS, and identify a novel pathway involved in HLHS pathogenesis.

Abstract Background The risk of recurrence after completion of curative‐intent treatment of colorectal cancer (CRC) is hard to predict. Post‐treatment assaying for circulating tumor DNA (ctDNA) is an encouraging approach for stratifying patients for therapy, but the prognostic value of this approach is less explored. This study aimed to determine if detection of methylated BCAT1 and IKZF1 following completion of initial treatment identified patients with a poorer recurrence‐free survival (RFS). Methods 142 CRC stage I‐III cases with at least 2 years of follow up (unless recurrence was evident sooner) and a methylated BCAT1/IKZF1 test result between 2 weeks and 12 months after completion of initial treatment were eligible for study inclusion. The association between BCAT1/IKZF1 and RFS was assessed by the log‐rank (Mantel‐Cox) method. Cox proportional hazard regression analysis was used for multivariable survival analysis. Results Thirty‐three (23.2%) had recurrence at a median 1.6y (interquartile range: 0.8–2.4). Methylated BCAT1/IKZF1 was detected in 19 of the 142 patients (13.4%) and was associated with a significant risk of recurrence (hazard ratio [HR] 5.7, 95%CI: 1.9–17.3, p = 0.002). Three‐year RFS for patients with or without detectable methylated BCAT1/IKZF1 was 56.5% and 83.3%, respectively. Multivariable analysis showed that detection of methylated BCAT1/IKZF1 (HR = 2.6, p = 0.049) and site of the primary tumor (HR = 4.2, p = 0.002) were the only significant prognostic indicators of poor RFS. Conclusions BCAT1/IKZF1 methylation testing after curative‐intent treatment is an independent prognostic indicator for RFS and identifies a subgroup at high risk. Personalized surveillance is warranted for patients with these ctDNA biomarkers detectable after curative‐intent treatment.

Abstract Point-of-care antigen-detecting rapid diagnostic tests (RDTs) to detect Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) represent a scalable tool for surveillance of active SARS-CoV-2 infections in the population. Data on the performance of these tests in real-world community settings are paramount to guide their implementation to combat the COVID-19 pandemic. We evaluated the performance characteristics of the CareStart COVID-19 Antigen test (CareStart) in a community testing site in Holyoke, Massachusetts. We compared CareStart to a SARS-CoV-2 reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) reference, both using anterior nasal swab samples. We calculated the sensitivity, specificity, and the expected positive and negative predictive values at different SARS-CoV-2 prevalence estimates. We performed 666 total tests on 591 unique individuals. 573 (86%) were asymptomatic. There were 52 positive tests by RT-qPCR. The sensitivity of CareStart was 49.0% (95% Confidence Interval (CI) 34.8–63.4) and specificity was 99.5% (95% CI 98.5–99.9). Among positive RT-qPCR tests, the median cycle threshold (Ct) was significantly lower in samples that tested positive on CareStart. Using a Ct ≤ 30 as a benchmark for positivity increased the sensitivity of the test to 64.9% (95% CI 47.5–79.8). Our study shows that CareStart has a high specificity and moderate sensitivity. The utility of RDTs, such as CareStart, in mass implementation should prioritize use cases in which a higher specificity is more important, such as triage tests to rule-in active infections in community surveillance programs.

Mito-SiPE is a mitochondrial DNA (mtDNA) enrichment method that can derive high-quality mtDNA for rare heteroplasmy analysis, without relying on PCR or probes.

Abstract This cost-outcome study estimated, from the perspective of the service provider, the total annual cost per client on antiretroviral therapy (ART) and total annual cost per client virally suppressed (defined as 18 years old) enrolled in a DSDM. The study found that retention in care was 98% for the sample as a whole [96–100%], and viral suppression, 91% [86-93%]. The mean cost to the provider (MOH or NGO implementers) was $152 per annum per client treated, ranging from $141 to $166. Differences among the models’ costs were largely due to clients’ ARV regimens and the proportions of clients on second line regimens. Service delivery costs, excluding ARVs, other medicines and laboratory tests, were modest, ranging from $9.66–16.43 per client per year. We conclude that differentiated ART service delivery in Uganda achieved excellent treatment outcomes at a cost similar to the standard of care. While large budgetary savings might not be immediately realized, the reallocation of “saved” staff time could improve health system efficiency and with their equivalent or better outcomes and large benefits to clients, client-centred differentiated models would nevertheless add great societal value.

We describe a case of mpox characterized by a circularly distributed facial rash but no identified risk factors. Fomite transmission of monkeypox virus from contaminated linen at a massage spa was suspected. Clinicians should consider mpox in patients with consistent clinical syndromes, even in the absence of epidemiologic risk factors.

Abstract Porphyry-type deposits are a vital source of green technology metals such as copper and molybdenum. They typically form in subduction-related settings from large, long-lived magmatic systems. The most widely accepted model for their formation requires that mantle-derived magmas undergo an increase in volatiles and ore-forming constituents in mid- to lower crustal reservoirs over millions of years, however, this is mostly based on observations from shallow, sporadically exposed parts of porphyry systems. To examine this paradigm, we have evaluated the timeframe and geochemical signatures of magmatism in a ~ 8 km palaeodepth cross-section through plutonic and volcanic rocks of the classic Yerington magmatic system, Nevada. We show that the magmas in the upper parts of the system (< 8 km) underwent a major and rapid change in chemistry over a period of

Introduction Men in sub-Saharan Africa are less likely than women to initiate antiretroviral therapy (ART) and more likely to have longer cycles of disengagement from ART programmes. Treatment interventions that meet the unique needs of men are needed, but they must be scalable. We will test the impact of various interventions on 6-month retention in ART programmes among men living with HIV who are not currently engaged in care (never initiated ART and ART clients with treatment interruption).Methods and analysis We will conduct a programmatic, individually randomised, non-blinded, controlled trial. ‘Non-engaged’ men will be randomised 1:1:1 to either a low-intensity, high-intensity or stepped arm. The low-intensity intervention includes one-time male-specific counseling+facility navigation only. The high-intensity intervention offers immediate outside-facility ART initiation+male-specific counselling+facility navigation for follow-up ART visits. In the stepped arm, intervention activities build in intensity over time for those who do not re-engage in care with the following steps: (1) one-time male-specific counselling+facility navigation→(2) ongoing male mentorship+facility navigation→(3) outside-facility ART initiation+male-specific counselling+facility navigation for follow-up ART visits. Our primary outcome is 6-month retention in care. Secondary outcomes include cost-effectiveness and rates of adverse events. The primary analysis will be intention to treat with all eligible men in the denominator and all men retained in care at 6 months in the numerator. The proportions achieving the primary outcome will be compared with a risk ratio, corresponding 95% CI and p value computed using binomial regression accounting for clustering at facility level.Ethics and dissemination The Institutional Review Board of the University of California, Los Angeles and the National Health Sciences Research Council in Malawi have approved the trial protocol. Findings will be disseminated rapidly in national and international forums and in peer-reviewed journals and are expected to provide urgently needed information to other countries and donors.Trial registration number NCT05137210.Date and version 5 May 2023; version 3.

Abstract Introduction South African youth and adolescents face a high burden of (Sexually Transmitted Infections) STIs, HIV and unintended pregnancies, but uptake of services remains low. To address this, tailored and scalable interventions are urgently needed. We developed a framework to fill the gap and translate the impact of facility‐level attributes into a cost‐effectiveness analysis for increasing HIV/contraceptive service uptake in adolescents using a discrete choice experiment (DCE). Methods We used a DCE (n = 805) conducted in Gauteng, South Africa, which found that staff attitude, confidentiality, Wi‐Fi, subsidized food, afternoon hours and youth‐only services were preferred attributes of health services. Based on this, we simulated the uptake of services adapted for these preferences. We divided preferences into modifiable attributes that could readily be adapted (e.g. Wi‐Fi), and challenging to modify (more nuanced attributes that are more challenging to cost and evaluate): staff attitude and estimated the incremental change in the uptake of services using adapted services. Costs for modifiable preferences were estimated using data from two clinics in South Africa (2019 US$). We determined the incremental cost‐effectiveness ratio (ICER) for additional adolescents using services of 15 intervention combinations, and report the results of interventions on the cost‐effectiveness frontier. Results Greatest projected impact on uptake was from friendly and confidential services, both of which were considered challenging to modify (18.5% 95% CI: 13.0%−24.0%; 8.4% 95% CI: 3.0%−14.0%, respectively). Modifiable factors on their own resulted in only small increases in expected uptake. (Food: 2.3% 95% CI: 4.0%−9.00%; Wi‐Fi: 3.0% 95% CI: −4.0% to 10.0%; Youth‐only services: 0.3% 95% CI: −6.0% to 7.0%; Afternoon services: 0.8% 95% CI: −6.0% to 7.0%). The order of interventions on the cost‐effectiveness frontier are Wi‐Fi and youth‐only services (ICER US$7.01−US$9.78 per additional adolescent utilizing HIV and contraceptive services), Wi‐Fi, youth‐only services and food (ICER US$9.32−US$10.45), followed by Wi‐Fi, youth‐only services and extended afternoon hours (ICER US$14.46–US$43.63). Conclusions Combining DCE results and costing analyses within a modelling framework provides an innovative way to inform decisions on effective resource utilization. Modifiable preferences, such as Wi‐Fi provision, youth‐only services and subsidized food, have the potential to cost‐effectively increase the proportion of adolescents accessing HIV and contraceptive services.

ObjectiveTo determine the relationship between constructive adolescent problem solving (positive problem-solving orientation and rational problem-solving style) and caregiver problem solving and collaborative involvement with primary caregiver among adolescents with spinal cord injuries (SCIs). Positive constructive adolescent problem solving was hypothesized to be predicted by more effective caregiver problem solving and higher collaborative involvement.MethodsParticipants in this cross-sectional study were 79 adolescent and primary caregiver dyads recruited from a pediatric rehabilitation care system in North America. All participants completed a standardized problem-solving instrument and adolescent participants completed an adapted measure of collaborative parent involvement.ResultsMore effective caregiver problem solving and adolescent perceptions of more collaboration with caregivers around SCI care were significantly associated with higher positive problem-solving orientation and higher rational problem-solving style among adolescents.ConclusionsResults underscore the importance of caregiver problem-solving skills and their collaboration with adolescents with SCI when addressing care needs. Clinically, findings highlight opportunities for parent involvement and skill-building as an important factor of rehabilitation for adolescents with SCI.

ObjectiveAdults with pediatric-onset spinal cord injury (SCI) require long-term care and demonstrate elevated risk of secondary health conditions and psychosocial challenges. Medical providers are typically found in more populous and wealthy areas, resulting in a relative lack of providers in rural areas, a discrepancy even more pronounced among specialty providers. As a result, those who reside in rural regions potentially have unmet medical needs, representing a significant public health concern. The purpose of this study was to assess differences between rural and urban-residing participants with pediatric-onset SCI in factors affecting healthcare usage (e.g., employment, income, access to private insurance, community integration) and long-term healthcare outcomes (i.e., secondary health conditions and psychosocial functioning).MethodsData were gathered from an ongoing study examining long-term outcomes of adults with pediatric-onset SCI. Participants (N = 490) completed measures of sociodemographics, injury characteristics, and medical outcomes. Participant zip codes were classified as rural or urban using the ProximityOne database based on the ZIP Code Tabulation Areas from the 2020 census.ResultsIndividuals residing in rural regions report lower levels of education, income, employment rates, private health insurance, and community integration (mobility, occupation, and social engagement), as well increased incidence of pressure injuries, urinary tract infections, hospitalizations, bowel incontinence, sleep difficulties, and perceived physical health. No differences in incidence of psychosocial functioning were identified.ConclusionMitigating identified disparities and obstacles to treatment of SCI due to residing in rural environments would result in important improvements in treatment outcomes and future prevention efforts of secondary health complications, improving the overall health of adults with pediatric-onset SCI.

Abstract We assess the skill of forecasts of Arctic September sea ice in the Sea Ice Outlook over 2008–2022. The multi‐model median June initialized forecast of September sea ice extent (SIE) is slightly more skilled (RMSE = 0.48 million km2) than a damped anomaly forecast, but July and August initialized forecasts (RMSE = 0.52 and 0.36 million km2 respectively) do not beat this benchmark. The skill of individual dynamical and statistical SIE forecasts is lower than the multi‐model median forecast skill. Overall skill is lower than expected from retrospective forecasts. Several forecasts initialized in early September 2021 and 2022 imply physically improbable values. Spatial forecasts of sea ice concentration show multi‐model forecast skill and an improvement in individual forecast skill in recent years. Initial conditions show large spread in sea ice volume and a positive correlation between initialized sea ice volume and September SIE forecast. Summer weather has an impact on forecast error.

Introduction: Rural‒urban smoking disparities have widened in recent years because smoking prevalence reductions have been experienced disproportionately among urban adults. Tobacco cessation programs that work in urban settings may not be reaching rural smokers or may need tailoring to be effective. Identifying smoking cessation preferences and barriers among rural smokers can facilitate the implementation of acceptable programs to address rural smoking-related disparities. Thus, the aim of this study was to examine tobacco cessation motivations, preferences, and barriers among rural smokers and to assess smokers’ likelihood to use various types of tobacco cessation programs. Methods: Using a cross-sectional study design, we distributed a self-administered survey to 100 smokers during regularly scheduled healthcare appointments at 3 rural Michigan practices from June to August 2019. We examined differences in participant characteristics by the readiness to quit using chi-square/Fisher's exact tests and described cessation motivations, preferences, and barriers to tobacco cessation among rural smokers. Results: Participants reporting readiness to quit were less likely to have smoking allowed in their home (31.7% vs. 75.0%; p=0.003) and had a higher prevalence of anxiety (62.1% vs. 6.3%; p=0.0001) and depression (49.2% vs. 18.8%; p=0.04) than those not ready to quit. Preferences were higher for nicotine replacement medications and reward-based approaches, with only 10% of participants being likely to use telephone-based quitlines. Conclusions: These findings suggest that provider referrals to nicotine replacement medications and reward-based approaches can be used to enhance tobacco cessation among rural smokers.

IMPORTANCE:. The need to understand how Community-based disparities impact morbidity and mortality in pediatric critical illness, such as traumatic brain injury. Test the hypothesis that ZIP code-based disparities in hospital utilization, including length of stay (LOS) and hospital costs, exist in a cohort of children with traumatic brain injury (TBI) admitted to a PICU using the Child Opportunity Index (COI). DESIGN:. Multicenter retrospective cohort study. SETTING:. Pediatric Health Information System (PHIS) database. PATIENTS:. Children 0–18 years old admitted to a PHIS hospital with a diagnosis of TBI from January 2016 to December 2020 requiring PICU care. To identify the most severely injured children, a study-specific definition of “Complicated TBI” was created based on radiology, pharmacy, and procedure codes. INTERVENTIONS:. None. Main Outcomes and Measures:. Using nationally normed ZIP code-level COI data, patients were categorized into COI quintiles. A low COI ZIP code has low childhood opportunity based on weighted indicators within educational, health and environmental, and social and economic domains. Population-averaged generalized estimating equation (GEE) models, adjusted for patient and clinical characteristics examined the association between COI and study outcomes, including hospital LOS and accrued hospital costs. The median age of this cohort of 8,055 children was 58 months (interquartile range [IQR], 8–145 mo). There were differences in patient demographics and rates of Complicated TBI between COI levels. The median hospital LOS was 3.0 days (IQR, 2.0–6.0 d) and in population-averaged GEE models, children living in very low COI ZIP codes were expected to have a hospital LOS 10.2% (95% CI, 4.1–16.8%; p = 0.0142) longer than children living in very high COI ZIP codes. For the 11% of children with a Complicated TBI, the relationship between COI and LOS was lost in multivariable models. COI level was not predictive of accrued hospital costs in this study. CONCLUSIONS:. Children with TBI requiring PICU care living in low-opportunity ZIP codes have higher injury severity and longer hospital LOS compared with children living in higher-opportunity ZIP codes. Additional studies are needed to understand why these differences exist.

Increased expression of the human telomere reverse transcriptase (hTERT) in tumors promotes tumor cell survival and diminishes the survival of patients. Cytosine-to-thymine (C-to-T) transition mutations (C250T or C228T) in the hTERT promoter create binding sites for transcription factors, which enhance transcription. The G-rich strand of the hTERT promoter can form G-quadruplex structures, whereas the C-rich strand can form an i-motif in which multiple cytosine residues are protonated. We considered the possibility that i-motif formation might promote cytosine deamination to uracil and C-to-T mutations. We computationally probed the accessibility of cytosine residues in an i-motif to attack by water. We experimentally examined regions of the C-rich strand to form i-motifs using pH-dependent UV and CD spectra. We then incubated the C-rich strand with and without the G-rich complementary strand DNA under various conditions, followed by deep sequencing. Surprisingly, deamination rates did not vary substantially across the 46 cytosines examined, and the two mutation hotspots were not deamination hotspots. The appearance of mutational hotspots in tumors is more likely the result of the selection of sequences with increased promoter binding affinity and hTERT expression.

Background: One per cent of women diagnosed with cervical cancer are pregnant or postpartum at the time of diagnosis. Therefore, awareness during pregnancy is of utmost significance. Objective: To determine predictors of knowledge of cervical cancer screening among pregnant women who attended antenatal clinics in Enugu, Nigeria. Materials and Methods: It was a descriptive cross-sectional study of 419 pregnant women who attended antenatal care at the University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu (139) and the Mother of Christ Specialist Hospital, Enugu (280). A multistage random sampling method was used to select the study centres and the participants. The questionnaires were administered by the interviewers and the data collected included sociodemographic characteristics, knowledge, and practice of cervical cancer screening. Data were analyzed using SPSS version 23. Results: The mean age of the participants was 28.86 ± 5.69, Christians (92.7%), and married (82.5%). Most of the respondents (82.3%) heard about cervical cancer screening methods through their gynecologists and of the 198 respondents who have heard about cervical cancer screening, 151 (76.3%) knew about Pap smear. One hundred thirty-eight (69.7%) of the participants believe that screening for premalignant lesions of the cervix can be performed during pregnancy. Only 37.9% of the participants had ever done Pap’s smear in the past 3 years. Respondents with higher social status (Civil/Public servants) were 10 times more likely to know about cervical cancer screening than those with lower social status (Trader/farmer/artisan) (P = 0.027, OR = 9.957, 95% CI = 1.301 – 76.191). Conclusion: Higher social status is more predictive of knowledge of cervical cancer screening amongst pregnant women attending antenatal clinics. Gynaecologist disseminate the information on cervical cancer screening more and Pap’s smear remain the main screening modality known to pregnant women. Efforts should be made by other health workers and the media to disseminate appropriate information on screening modalities for the prevention of cervical cancer

During July 2021, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.617.2 variant infections, including vaccine breakthrough infections, occurred after large public gatherings in Provincetown, Massachusetts, USA, prompting a multistate investigation. Public health departments identified primary and secondary cases by using coronavirus disease surveillance data, case investigations, and contact tracing. A primary case was defined as SARS-CoV-2 detected

Maternity waiting homes (MWHs) are one strategy to improve access to skilled obstetric care in low resource settings such as Zambia. The Maternity Homes Access in Zambia project built 10 MWHs at rural health centers in Zambia for women awaiting delivery and postnatal care (PNC) visits. The objective of this paper is to summarize the costs associated with setup of 10 MWHs, including infrastructure, furnishing, stakeholder engagement, and activities to build the capacity of local communities to govern MWHs. We do not present operational costs after setup was complete. We used a retrospective, top-down program costing approach. We reviewed study documentation to compile planned and actual costs by site. All costs were annuitized using a 3% discount rate and organized by cost categories: (1) Capital: infrastructure and furnishing, and (2) Installation: capacity building activities and stakeholder engagement. We assumed lifespans of 30 years for infrastructure; 5 years for furnishings; and 3 years for installation activities. Annuitized costs were used to estimate cost per night stayed and per visit for delivery and PNC-related stays. We also modeled theoretical utilization and cost scenarios. The average setup cost of one MWH was $85,284 (capital: 76%; installation: 24%). Annuitized setup cost per MWH was USD$12,516 per year. At an observed occupancy rate of 39%, setup cost per visit to the MWH was USD$70, while setup cost per night stayed was USD$6. The cost of stakeholder engagement activities was underbudgeted by half at the beginning of this project.This analysis serves as a planning resource for governments and implementers that are considering MWHs as a component of their overall maternal and child health strategy. Planning considerations should include the annuitized cost, value of capacity building and stakeholder engagement, and that cost per bed night and visit are dependent upon utilization.

Introduction Intimate partner violence (IPV) is a barrier to consistent HIV treatment in South Africa. Previous trials have established that the Common Elements Treatment Approach (CETA), a cognitive-behavioural-based intervention, is effective in reducing mental and behavioural health problems but has not been trialled for effectiveness in improving HIV outcomes. This paper describes the protocol for a randomised trial that is testing the effectiveness of CETA in improving HIV treatment outcomes among women experiencing IPV in South Africa.Methods and analysis We are conducting a randomised trial among HIV-infected women on antiretroviral therapy, who have experienced sexual and/or physical IPV, to test the effect of CETA on increasing retention and viral suppression and reducing IPV. Women living with HIV who have an unsuppressed viral load or are at high risk for poor adherence and report experiencing recent IPV, defined as at least once within in the last 12 months, will be recruited from HIV clinics and randomised 1:1 to receive CETA or an active attention control (text message reminders). All participants will be followed for 24 months. Follow-up HIV data will be collected passively using routinely collected medical records. HIV outcomes will be assessed at 12 and 24 months post-baseline. Questionnaires on violence, substance use and mental health will be administered at baseline, post-CETA completion and at 12 months post-baseline. Our primary outcome is retention and viral suppression (

Objective: To assess the association of age at pediatric-onset spinal cord injury (SCI) and years of manual wheelchair use with shoulder dynamics. Design: Upper extremity kinematics and hand-rim kinetics were obtained during manual wheelchair propulsion. An inverse dynamics model computed three-dimensional acromioclavicular, sternoclavicular, and glenohumeral joint dynamics. Linear mixed effects models evaluated the association of age at injury onset and years of wheelchair use with shoulder dynamics. Setting: Motion laboratory within a children's hospital. Participants: Seventeen manual wheelchair users (N=17; 6 female, 11 male; mean age: 17.2 years, mean age at SCI onset: 11.5 years) with pediatric-onset SCI (levels: C4-T11) and International Standards for Neurological Classification of SCI grades: A (11), B (3), C (2), and N/A (2). Interventions: Not applicable. Main Outcome Measures: Acromioclavicular, sternoclavicular, and glenohumeral angles and ranges of motion, and glenohumeral forces and moments. Results: We observed a decrease in maximum acromioclavicular upward rotation (ß [95% confidence interval {CI}]=3.02 [0.15,5.89], P=.039) and an increase in acromioclavicular downward/upward rotation range of motion (ß [95% CI]=0.44 [0.08,0.80], P=.016) with increasing age at SCI onset. We found interactions between age at onset and years of use for maximum glenohumeral abduction (ß [95% CI]=0.16 [0.03,0.29], P=.017), acromioclavicular downward/upward rotation range of motion (ß [95% CI]=-0.05 [-0.09,-0.01], P=.008), minimum acromioclavicular upward rotation (ß [95% CI]=-0.34 [-0.64,-0.04], P=.026). A decrease in glenohumeral internal rotation moment (ß [95% CI]=-0.09 [-0.17,-0.009], P=.029) with increasing years of use was found. Conclusions: Age at injury and the years of wheelchair use are associated with shoulder complex biomechanics during wheelchair propulsion. These results are noteworthy, as both age at SCI onset and years of wheelchair use are considered important factors in the incidence of shoulder pain. These results suggest that investigations of biomechanical changes over the lifespan are critical.

Subcutaneous phaeohyphomycosis typically affects immunocompetent individuals following traumatic inoculation. Severe or disseminated infection can occur in CARD9 deficiency or after transplantation, but the mechanisms protecting against phaeohyphomycosis remain unclear. We evaluated a patient with progressive, refractory Corynespora cassiicola phaeohyphomycosis and found that he carried biallelic deleterious mutations in CLEC7A encoding the CARD9-coupled, β-glucan–binding receptor, Dectin-1. The patient’s PBMCs failed to produce TNF-α and IL-1β in response to β-glucan and/or C. cassiicola. To confirm the cellular and molecular requirements for immunity against C. cassiicola, we developed a mouse model of this infection. Mouse macrophages required Dectin-1 and CARD9 for IL-1β and TNF-α production, which enhanced fungal killing in an interdependent manner. Deficiency of either Dectin-1 or CARD9 was associated with more severe fungal disease, recapitulating the human observation. Because these data implicated impaired Dectin-1 responses in susceptibility to phaeohyphomycosis, we evaluated 17 additional unrelated patients with severe forms of the infection. We found that 12 out of 17 carried deleterious CLEC7A mutations associated with an altered Dectin-1 extracellular C-terminal domain and impaired Dectin-1–dependent cytokine production. Thus, we show that Dectin-1 and CARD9 promote protective TNF-α– and IL-1β–mediated macrophage defense against C. cassiicola. More broadly, we demonstrate that human Dectin-1 deficiency may contribute to susceptibility to severe phaeohyphomycosis by certain dematiaceous fungi.

Hepatitis E virus is a common cause of acute viral hepatitis. We analyzed reports of hepatitis E outbreaks among forcibly displaced populations in sub-Saharan Africa during 2010–2020. Twelve independent outbreaks occurred, and >30,000 cases were reported. Transmission was attributed to poor sanitation and overcrowding.